Cesium carbonate → (R)-N-(6,7-dichloroisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 1875986Notes

Reaction equation

HRID 1875986 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N:7][C:6]([N:13]=[C:14]=S)=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH2:24][CH2:25][C@@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N:7][C:6]([NH:13][C:14]1[O:34][C@:26]3([CH2:25][N:24]=1)[CH:31]1[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]1)[CH2:27]3)=[CH:5]2

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574766036,7-Dichloro-3-isothiocyanatoisoquinolineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58087994(R)-N-(6,7-dichloroisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 61.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
70 °C

Procedure

To 6,7-dichloro-3-isothiocyanatoisoquinoline (0.13 g, 0.510 mmol) in DMF (10 mL) was added cesium carbonate (0.42 g, 1.27 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.118 g, 0.515 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with DMF (10 mL) and N,N′-diisopropylcarbodiimide (0.238 mL, 1.529 mmol). The reaction was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated to yield the crude product, which was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(6,7-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.12 g, 0.312 mmol, 61.2% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.03 (s, 1H), 8.87 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.24 (s, 1H), 3.88-4.06 (m, 1H), 3.60-3.74 (m, 1H), 3.42 (d, J=14.65 Hz, 1H), 2.82-3.15 (m, 5H), 2.23-2.34 (m, 1H), 2.18 (s, 1H), 1.72-1.87 (m, 1H), 1.48-1.70 (m, 2H). MS (LC/MS) R.T.=1.63; [M+H]+=377.1.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. customThe crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)
  4. temperatureThe reaction was heated to 90° C. for 18 hours
  5. temperatureThe reaction was cooled to room temperature
  6. concentrationconcentrated
  7. customto yield the crude product, which
  8. customwas purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)

Sources & evidence

ORD record
ord-9ae3ec001b0244868d71956104393451
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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